趙凈穎，段小花,2，王秋婷，黃英，賈俊靜，豆騰飛

動(dòng)物骨代謝相關(guān)信號(hào)通路研究進(jìn)展

趙凈穎1，段小花1,2，王秋婷1，黃英1，賈俊靜1，豆騰飛1

1. 云南農(nóng)業(yè)大學(xué)動(dòng)物科學(xué)技術(shù)學(xué)院，昆明 650201 2. 云南中醫(yī)學(xué)院，昆明 650500

骨骼是組成脊椎動(dòng)物內(nèi)骨骼的堅(jiān)硬器官，對(duì)機(jī)體起著運(yùn)動(dòng)、支撐和保護(hù)的作用。骨骼處于骨形成和骨吸收兩種活動(dòng)所組成的骨代謝的動(dòng)態(tài)平衡狀態(tài)，這種平衡對(duì)于維持骨量和礦物質(zhì)穩(wěn)態(tài)至關(guān)重要。在動(dòng)物骨代謝過(guò)程中，存在著眾多調(diào)節(jié)骨形成和骨吸收的信號(hào)通路，如BMP (bone morphogenetic protein)/SMADs、TGF-β (transforming growth factor β)、Wnt/β-catenin、OPG (osteoprotegerin)/RANKL (receptor activator of NF-κB ligand)/ RANK (receptor activator of NF-κB)、FGF (fibroblast growth factor)和Notch信號(hào)通路等。這些信號(hào)通路具有復(fù)雜的調(diào)控機(jī)制，參與骨代謝過(guò)程的調(diào)節(jié)。本文綜述了在動(dòng)物骨代謝過(guò)程中起關(guān)鍵調(diào)節(jié)作用的相關(guān)信號(hào)通路的作用機(jī)制及研究進(jìn)展，以期為動(dòng)物骨代謝研究奠定基礎(chǔ)。

骨代謝；信號(hào)通路；骨形成；骨吸收

骨骼是脊椎動(dòng)物機(jī)體重要的剛性組織，主要由磷酸鈣礦物質(zhì)和I型膠原組成，對(duì)動(dòng)物機(jī)體起到支撐、保護(hù)以及運(yùn)動(dòng)等作用。骨骼系統(tǒng)的發(fā)育和維持受遺傳及環(huán)境等因素的影響[1]，其中遺傳因素是影響骨骼系統(tǒng)發(fā)育的重要因素，其對(duì)骨骼生長(zhǎng)發(fā)育的影響在動(dòng)物的整個(gè)生命過(guò)程中均有體現(xiàn)，包括骨相關(guān)信號(hào)通路調(diào)控機(jī)制、基因作用的發(fā)育時(shí)機(jī)、骨相關(guān)基因產(chǎn)物的表觀遺傳修飾等[2]。

骨骼發(fā)育過(guò)程包括膜內(nèi)骨化和軟骨內(nèi)骨化兩種方式[3]。在膜內(nèi)骨化過(guò)程中，間充質(zhì)干細(xì)胞(mesen-chymal stem cell, MSC)直接分化成成骨細(xì)胞(osteo-blast, OB)。膜內(nèi)骨化主要發(fā)生在顱頂骨部位。在軟骨內(nèi)骨化過(guò)程中，間充質(zhì)干細(xì)胞發(fā)生增殖分化形成軟骨，隨后被礦化骨所取代。軟骨內(nèi)骨化發(fā)生在顱底和顱骨后部、軸向骨和四肢骨。發(fā)育結(jié)束進(jìn)入穩(wěn)態(tài)維持的骨骼處于骨形成和骨吸收所組成的骨代謝動(dòng)態(tài)平衡狀態(tài)，其中骨形成過(guò)程是由MSC衍生的OB介導(dǎo)，骨吸收過(guò)程是由造血干細(xì)胞(hematopoietic stem cell, HSC)衍生的破骨細(xì)胞(osteoclast，OC)介導(dǎo)。骨吸收與骨形成之間的平衡對(duì)于維持骨量和維持全身礦物質(zhì)穩(wěn)態(tài)至關(guān)重要，因此可以保持骨骼健康。一旦這種平衡狀態(tài)被破壞，骨骼便會(huì)處于病理狀態(tài)，也稱骨代謝性疾病，如高破骨細(xì)胞活性或低成骨細(xì)胞活性導(dǎo)致的低骨量(骨質(zhì)減少)，以及低破骨細(xì)胞活性或高成骨細(xì)胞活性導(dǎo)致的高骨量(骨硬化)[4]。

在動(dòng)物骨骼生長(zhǎng)發(fā)育和骨代謝過(guò)程中，存在著生長(zhǎng)因子、細(xì)胞因子、酶等眾多調(diào)控因子，而這些調(diào)控因子通過(guò)相關(guān)的信號(hào)通路參與骨形成和骨吸收過(guò)程，如BMP (bone morphogenetic protein)/Smads、TGF-β (transforming growth factor β)、Wnt/β-catenin、OPG (osteoprotegerin)/RANKL (receptor activator of NF-κB ligand)/RANK (receptor activator of NF-κB)、FGF (fibroblast growth factor)和Notch信號(hào)通路等。其中，BMP/Smads信號(hào)通路影響成骨細(xì)胞分化及骨形成，TGF-β信號(hào)通路參與調(diào)控成骨過(guò)程中細(xì)胞的活動(dòng)和代謝，Wnt/β-catenin信號(hào)通路調(diào)控骨代謝的平衡，OPG/RANKL/RANK信號(hào)通路可以維持骨骼穩(wěn)態(tài)，F(xiàn)GF信號(hào)通路和Notch信號(hào)通路參與成骨細(xì)胞分化。本文介紹了參與動(dòng)物骨代謝的信號(hào)通路相關(guān)研究進(jìn)展，闡明這些信號(hào)通路在調(diào)節(jié)骨形成和骨吸收方面的作用機(jī)制，可以為臨床有效防治骨異常性疾病提供理論依據(jù)。

1 影響動(dòng)物骨代謝的關(guān)鍵信號(hào)通路

動(dòng)物骨代謝的調(diào)控是一個(gè)非常復(fù)雜的過(guò)程，有眾多的調(diào)節(jié)因子及信號(hào)途徑參與。這些途徑各自具有復(fù)雜的調(diào)控機(jī)制，單獨(dú)或共同參與動(dòng)物骨代謝的調(diào)控。近年來(lái)眾多研究表明，動(dòng)物骨代謝的平衡主要由BMP/Smads、TGF-β、Wnt/β-catenin、OPG/RANKL/ RANK和FGF等多條關(guān)鍵信號(hào)通路參與調(diào)控。

1.1 BMP/Smads信號(hào)通路

在骨骼發(fā)育過(guò)程中，多條信號(hào)通路參與調(diào)節(jié)成骨與破骨過(guò)程的平衡，而最早發(fā)現(xiàn)和確認(rèn)的最重要的一條通路是影響成骨細(xì)胞分化及骨形成的關(guān)鍵信號(hào)通路——BMP/Smads信號(hào)通路[5,6]。

骨形態(tài)發(fā)生蛋白(bone morphogenetic protein, BMPs)是轉(zhuǎn)化生長(zhǎng)因子β(transform growth factor β, TGF-β)超家族的成員，是骨骼發(fā)育的重要生長(zhǎng)因子，具有增強(qiáng)骨髓干細(xì)胞向成骨細(xì)胞分化的能力，從而促進(jìn)骨骼的生長(zhǎng)發(fā)育[5]。在已發(fā)現(xiàn)的20余種亞型中，BMP2、4、5、6、7、9等均對(duì)成骨細(xì)胞分化有調(diào)節(jié)作用[6~8]。其中BMP2因具有增強(qiáng)骨形成及代謝的作用而成為研究熱點(diǎn)。BMP2能夠誘導(dǎo)間充質(zhì)干細(xì)胞的增殖、遷移以及向成骨細(xì)胞的分化[8,9]，且能夠協(xié)同其他成骨因子共同刺激成骨細(xì)胞增殖，增強(qiáng)成骨細(xì)胞活性，加速骨重建[10]。

BMP/Smads信號(hào)通路由BMPs及其受體、Smad蛋白和相關(guān)轉(zhuǎn)錄因子組成。BMP2通過(guò)自分泌或旁分泌形式釋放后，其單體可通過(guò)二硫鍵連接形成二聚體，再結(jié)合BMPs受體。BMPs受體是絲氨酸/蘇氨酸激酶受體，包括I型受體(BMPR-IA、BMPR-IB和ACVR-I)和II型受體(BMPR-II、ActR-IIA和ActR-IIB)[11]。BMP2先結(jié)合BMPR-II，發(fā)生自身磷酸化而被激活，繼而磷酸化BMPR-I，使BMPR-I激活[12~14]，下游Smads 信號(hào)Smad1/5/8被BMPR-I受體激活并和受體形成短暫復(fù)合物，使其與Smad4結(jié)合，轉(zhuǎn)移至核內(nèi)，轉(zhuǎn)錄激活成骨分化基因，如上調(diào)核心結(jié)合蛋白因子2 ()[15,16]、成骨細(xì)胞特異性轉(zhuǎn)錄因子Osterix ()[17]和同源盒基因[18]等，促進(jìn)成骨細(xì)胞分化。而Smad6和Smad7則參與了骨形態(tài)發(fā)生蛋白信號(hào)傳導(dǎo)的負(fù)調(diào)控[19]。

Dallari等[20]和Yang等[21]在人類骨骼疾病的臨床研究中發(fā)現(xiàn)骨質(zhì)疏松性骨折患者常伴有堿性磷酸酶活性下降的現(xiàn)象，而導(dǎo)致堿性磷酸酶活性下降的重要原因是等成骨基因表達(dá)不足，并且存在抑制軟骨細(xì)胞向成骨細(xì)胞的分化并伴有成骨細(xì)胞凋亡的增加現(xiàn)象。Zappitelli等[22]在小鼠()細(xì)胞實(shí)驗(yàn)中的研究顯示，上調(diào)基因的表達(dá)可提高成骨細(xì)胞特定標(biāo)志物的表達(dá)。Li等[19]和Zarrinkalam等[23]在山羊()的活體實(shí)驗(yàn)研究中發(fā)現(xiàn)，注射人重組的BMP2可提高骨密度，并可以治療骨質(zhì)疏松山羊腰椎骨缺損處；Cipitria等[24]研究表明注射人重組的BMP7可提高山羊脛骨的韌性和強(qiáng)度。Mizrahi等[25]在豬()的間充質(zhì)干細(xì)胞研究中發(fā)現(xiàn)，人重組的BMP6比BMP2更加有效地誘導(dǎo)成骨分化，促進(jìn)骨骼的形成。在BMP2/ Smads信號(hào)通路中，存在眾多的相關(guān)調(diào)控因子。研究發(fā)現(xiàn)，泛素化調(diào)節(jié)因子(Smurf)與BMP2激活的Smad1、Smad5相互作用并調(diào)節(jié)成骨細(xì)胞特異性轉(zhuǎn)錄因子Runx2降解[26]，并且Smad6與Smurf的協(xié)同作用可下調(diào)Runx2蛋白水平，負(fù)向調(diào)控BMP/Smads信號(hào)通路[27]。而I型多發(fā)性內(nèi)分泌腺瘤腫瘤抑制基因產(chǎn)物(Menin)可增強(qiáng)BMP2誘導(dǎo)的的轉(zhuǎn)錄活性。膠原三股螺旋重復(fù)蛋白1 (collagen triple helix repeat containing 1, Cthrc1)可正向調(diào)節(jié)OB骨形成，從而使骨量增加。Takeshita等[28]研究發(fā)現(xiàn)，缺失的小鼠在生長(zhǎng)初期，堿性磷酸酶(alkaline phosphatase, ALP)和骨鈣素(bone gamma- carboxyglutamic-acid-containing proteins, BGP)表達(dá)減少。對(duì)豬和羊的研究發(fā)現(xiàn)，基因是BMPs的拮抗劑，可調(diào)節(jié)BMPs對(duì)骨骼的作用，調(diào)節(jié)骨生長(zhǎng)發(fā)育的重要細(xì)胞因子[29,30]。

除BMP/Smads信號(hào)通路相關(guān)調(diào)控因子以外，一些外在因素也可通過(guò)調(diào)節(jié)BMP/Smads信號(hào)通路來(lái)促進(jìn)動(dòng)物骨骼的生長(zhǎng)發(fā)育。Feng等[31]對(duì)大鼠()細(xì)胞的研究顯示，辛伐他汀(simvastain)可促進(jìn)骨質(zhì)疏松癥(osteoporosi, OP)大鼠的關(guān)鍵成骨分化相關(guān)因子，骨保護(hù)素(osteoprotegerin,)，骨橋蛋白(osteopontin,)和的mRNA表達(dá)水平升高，可以通過(guò)BMP/Smads信號(hào)通路促進(jìn)OP大鼠模型中MSCs向OB分化。Chai等[32]在去卵巢大鼠的研究中發(fā)現(xiàn)，傳統(tǒng)中藥配方骨疏康處理組通過(guò)上調(diào)BMP2，磷酸化Smad1和磷酸化Smad5 (p-Smad1/5)，升高Osterix和Runx2的表達(dá)來(lái)顯著增強(qiáng)BMP/Smads信號(hào)通路，促進(jìn)骨形成。Yu等[33]研究顯示，大豆()苷元通過(guò)激活BMP/Smads途徑促進(jìn)成骨細(xì)胞增殖和分化，具體表現(xiàn)為上調(diào)、、基因的表達(dá)以及Runx2和Smad1蛋白的表達(dá)?？梢?jiàn)，BMP/Smads信號(hào)通路的激活可以促進(jìn)動(dòng)物成骨細(xì)胞的增殖、分化及骨形成。

1.2 TGF-β信號(hào)通路

骨骼中TGF-β家族成員參與了整個(gè)成骨過(guò)程中細(xì)胞活動(dòng)和代謝的調(diào)控。TGF-β家族由3種亞型組成：TGF-β1、TGF-β2和TGF-β3[34]，均在骨中表達(dá)。TGF-β與其結(jié)合蛋白(LTBP)結(jié)合形成復(fù)合物，由OB分泌，可以與細(xì)胞外基質(zhì)(extracellular matrix, ECM)成分(纖維連接蛋白、纖顫蛋白1和整合素等)相互作用，增強(qiáng)成骨細(xì)胞分化，促進(jìn)骨骼發(fā)育[35]。Dünker等[36]研究表明，TGF-β2和TGF-β3雙基因敲除小鼠遠(yuǎn)端部分骨量丟失，特別是缺失的小鼠在膜內(nèi)和軟骨內(nèi)骨化方面表現(xiàn)出嚴(yán)重的骨骼異常。

在骨基質(zhì)合成終止后，成骨細(xì)胞發(fā)生凋亡或分化為骨細(xì)胞(骨襯細(xì)胞)。成熟的TGF-β通過(guò)阻止成骨細(xì)胞凋亡來(lái)調(diào)控成骨細(xì)胞的存活。骨髓巨噬細(xì)胞是破骨細(xì)胞的前體，而TGF-β直接作用于骨髓巨噬細(xì)胞，促進(jìn)破骨細(xì)胞生成。Yasui等[37]研究表明，TGF-β誘導(dǎo)Smad2/3與泛素連接酶TRAF6 (TNF receptor associated factor 6)之間的分子相互作用，對(duì)于RANKL誘導(dǎo)的破骨細(xì)胞信號(hào)通路至關(guān)重要。此外，成骨細(xì)胞可產(chǎn)生和巨噬細(xì)胞集落刺激因子(macrophage colony stimulating factor,)。因此，TGF-β對(duì)破骨細(xì)胞的作用也來(lái)源于成骨細(xì)胞。TGF-β刺激成骨細(xì)胞不僅表達(dá)I型膠原、ALP、BGP等成骨功能蛋白，還表達(dá)、、等破骨細(xì)胞調(diào)控基因[38]。TGF-β對(duì)破骨細(xì)胞生成的影響與劑量有關(guān)，低劑量TGF-β通過(guò)增加M-CSF的表達(dá)和前列腺素的產(chǎn)生，以及RANKL與OPG的比值來(lái)增強(qiáng)破骨細(xì)胞的生成[39]，而高濃度TGF-β則通過(guò)增加的表達(dá)來(lái)抑制和的表達(dá)[40]。由于OPG是RANKL的高親和力配體，是成骨細(xì)胞產(chǎn)生的RANKL的可溶性抑制劑，因此TGF-β對(duì)成骨細(xì)胞介導(dǎo)的破骨細(xì)胞的作用可能是骨重建的負(fù)反饋?zhàn)饔谩?/p>

Shi等[41]研究發(fā)現(xiàn)，用TGF-β信號(hào)抑制劑SB431542處理的骨髓間充質(zhì)干細(xì)胞(mesenchymal stem cells, MSC)，移植到豬上頜骨缺損處，可以促進(jìn)成骨分化增加，成功修復(fù)小型豬嚴(yán)重的頜面部骨缺損。Zeng等[42]通過(guò)細(xì)胞實(shí)驗(yàn)發(fā)現(xiàn)miR-23a簇(miR-23a-24-2-27a簇)通過(guò)靶向TGF-β途徑的負(fù)調(diào)節(jié)劑Prdm16來(lái)調(diào)節(jié)TGF-β信號(hào)通路，從而促進(jìn)小鼠骨細(xì)胞的分化。Xu等[43]研究表明，系統(tǒng)或局部阻斷軟骨中TGF-β活性可減輕類風(fēng)濕關(guān)節(jié)炎(rheumatoid arthritis, RA)關(guān)節(jié)軟骨退變，表明軟骨中TGF-β的異常激活與RA關(guān)節(jié)軟骨退變的發(fā)生有關(guān)?？梢?jiàn)，TGF-β對(duì)動(dòng)物成骨分化起著負(fù)反饋?zhàn)饔谩?/p>

1.3 Wnt/β-catenin信號(hào)通路

Wnt信號(hào)通路已成為骨代謝平衡的關(guān)鍵調(diào)控信號(hào)通路[44]。Wnt信號(hào)控制胚胎發(fā)育和細(xì)胞增殖、分化、遷移等多個(gè)過(guò)程。β-catenin是調(diào)控Wnt信號(hào)的必要調(diào)控因子。一旦Wnt蛋白與Frizzled受體、低密度脂蛋白相關(guān)蛋白受體(Lrp5或Lrp6)結(jié)合，β-catenin將逃脫降解機(jī)制，轉(zhuǎn)移到細(xì)胞核并與轉(zhuǎn)錄調(diào)節(jié)因子Tcf/Lef相互作用，激活Wnt靶基因的轉(zhuǎn)錄。在骨質(zhì)疏松/高骨密度綜合征中，Lrp5的功能發(fā)生缺陷[45,46]。β-catenin信號(hào)對(duì)成骨細(xì)胞發(fā)揮細(xì)胞環(huán)境相關(guān)的功能取決于分化的階段。在早期階段，β-catenin在前成骨細(xì)胞中失活，導(dǎo)致成骨細(xì)胞分化受阻，從而致使骨骼中缺乏成熟的成骨細(xì)胞[47~50]。然而，在后期階段，β-catenin在成熟的成骨細(xì)胞和骨細(xì)胞中失活并不影響成骨細(xì)胞分化和骨形成，而是通過(guò)增加破骨細(xì)胞分化和骨吸收導(dǎo)致骨量降低[51~53]。在Wnt/β-catenin信號(hào)通路中，甲狀旁腺激素和機(jī)械負(fù)荷等因素可下調(diào)骨細(xì)胞中基因并增強(qiáng)β-catenin信號(hào)[54~56]。編碼硬化蛋白，是一種有效的骨形成抑制劑，通過(guò)與Lrp5/6結(jié)合來(lái)拮抗Wnt信號(hào)，而硬化蛋白表達(dá)的缺失是導(dǎo)致高骨量疾病范·巴克病(van Buchem)和硬化性骨化病的原因[57,58]。因此，Wnt信號(hào)的激活對(duì)動(dòng)物骨代謝的調(diào)節(jié)起重要作用。

Tu等[43]研究表明，激活β-catenin的小鼠表現(xiàn)出四肢骨骼骨礦物質(zhì)密度增加，骨小梁數(shù)量、骨松質(zhì)密度、骨形成標(biāo)記物顯著增加，且骨膜骨形成率明顯升高；骨骼中Wnt信號(hào)靶向基因、成骨細(xì)胞和骨細(xì)胞標(biāo)記、原骨細(xì)胞因子和抗破骨細(xì)胞因子含量升高。因此，激活骨細(xì)胞中的Wnt/β-catenin信號(hào)可增加成骨細(xì)胞的增殖、分化，從而促進(jìn)骨量增加?？梢?jiàn)，β-catenin可激活骨細(xì)胞和成骨細(xì)胞等骨細(xì)胞的合成代謝是骨骼中Wnt/β-catenin信號(hào)促進(jìn)骨形成的重要原因。Wang等[59]研究發(fā)現(xiàn)，脂聯(lián)素(adiponectin)轉(zhuǎn)基因的BMSCs中的和細(xì)胞周期蛋白D1 ()基因及其蛋白表達(dá)水平較高，且脂聯(lián)素治療組小鼠觀察到更多新骨形成，表明脂聯(lián)素可促進(jìn)BMSCs成骨分化和成骨，而Wnt/β-catenin途徑參與脂聯(lián)素的成骨作用。Zhu等[60]在體外培養(yǎng)的BMSCs中發(fā)現(xiàn)，梓醇(catalpol)可顯著增強(qiáng)成骨細(xì)胞特異性基因表達(dá)、堿性磷酸酶活性和鈣沉積，可通過(guò)激活Wnt/β-catenin途徑促進(jìn)BMSCs的成骨分化。Mola-goda等[61]發(fā)現(xiàn)太平洋牡蠣()提取物可以在斑馬魚(yú)()中通過(guò)誘導(dǎo)Wnt/β-catenin途徑來(lái)促進(jìn)幼體骨礦化及尾鰭再生。因此，在動(dòng)物骨骼生長(zhǎng)發(fā)育中可通過(guò)激活Wnt/ β-catenin信號(hào)通路來(lái)促進(jìn)成骨分化，促進(jìn)骨量增加。

1.4 OPG/RANKL/RANK信號(hào)通路

骨轉(zhuǎn)換(bone turnover)取決于成骨細(xì)胞的骨形成和破骨細(xì)胞的骨吸收之間的平衡。骨量丟失和骨質(zhì)疏松癥的發(fā)生是骨吸收大于骨形成導(dǎo)致的。OPG、細(xì)胞核因子-κB受體活化因子(RANK)和RANK配體(RANKL)是偶聯(lián)成骨細(xì)胞、基質(zhì)細(xì)胞和破骨細(xì)胞分化、活化及生物活性的3種主要細(xì)胞因子，OPG/ RANKL/RANK信號(hào)通路是破骨細(xì)胞生物學(xué)的基礎(chǔ)，在骨代謝中起十分重要的作用[62]。大量研究表明，人類及動(dòng)物代謝性骨病與這一系統(tǒng)的改變有關(guān)[63~65]。

OPG是腫瘤壞死因子(tumor necrosis factor, TNF)受體家族成員，又稱破骨細(xì)胞生成抑制因子或TNF受體樣分子，是一種通過(guò)抑制破骨細(xì)胞分化和活化來(lái)調(diào)節(jié)骨量的分泌蛋白。RANKL是腫瘤壞死因子超家族的一員，已被證明既能介導(dǎo)破骨細(xì)胞生成，又能激活成熟破骨細(xì)胞。RANK是RANKL的受體，結(jié)合RANKL發(fā)揮生物學(xué)功能。在骨組織中，RANKL由多種細(xì)胞表達(dá)，包括成骨細(xì)胞、骨細(xì)胞和免疫細(xì)胞，尤其在成骨細(xì)胞和骨細(xì)胞中的表達(dá)較高[66]。RANKL結(jié)合并激活其位于破骨細(xì)胞祖細(xì)胞和成熟破骨細(xì)胞上的受體RANK。RANK刺激導(dǎo)致前破骨細(xì)胞分化為活性破骨細(xì)胞，活性破骨細(xì)胞重新吸收礦化骨基質(zhì)。RANKL的活化優(yōu)先表達(dá)于成骨前細(xì)胞的細(xì)胞膜上，而其特異性受體RANK則表達(dá)于破骨細(xì)胞前體細(xì)胞的細(xì)胞膜上。RANKL與RANK的結(jié)合導(dǎo)致破骨前細(xì)胞分化、形成、融合和存活[67]。RANK- RANKL相互作用是破骨細(xì)胞形成的必要條件。

研究表明，缺失RANKL的動(dòng)物在缺乏骨基質(zhì)或成骨細(xì)胞的情況下，無(wú)法產(chǎn)生破骨細(xì)胞，而提供外源性RANKL可刺激體外破骨細(xì)胞生成[68]?；|(zhì)細(xì)胞和包括成骨細(xì)胞系在內(nèi)的其他類型細(xì)胞分泌的OPG，可競(jìng)爭(zhēng)性地結(jié)合RANKL，阻斷RANK對(duì)破骨細(xì)胞的作用，進(jìn)而抑制破骨細(xì)胞的活化，進(jìn)而抑制破骨和骨溶解。過(guò)表達(dá)的小鼠導(dǎo)致嚴(yán)重骨丟失和成熟破骨細(xì)胞減少實(shí)驗(yàn)，表明OPG可作為破骨細(xì)胞生成抑制劑[69]，而RANKL缺失的小鼠表現(xiàn)出嚴(yán)重的骨丟失，并且由于不能支持破骨細(xì)胞的生成而完全缺乏破骨細(xì)胞[70]。然而，Liu等[71]研究表明敲除的小鼠骨質(zhì)疏松，骨密度降低，骨折發(fā)生率高，通過(guò)靜脈注射重組OPG蛋白可逆轉(zhuǎn)其病理。因此，OPG的存在對(duì)維持正常骨量是絕對(duì)必要的。另外，有研究表明，作為破骨生成促進(jìn)因子的和破骨生成抑制因子的表達(dá)水平的平衡決定了骨吸收的程度，RANKL上調(diào)和OPG下調(diào)都會(huì)導(dǎo)致骨質(zhì)流失[72]，且OPG/RANKL比值的失衡可能導(dǎo)致骨量的丟失[73]。

Huang等[74]對(duì)家雞()的研究表明，OPG/RANKL平衡的破壞導(dǎo)致骨形成改變，引起雞脛骨結(jié)構(gòu)改變、脛骨質(zhì)量降低，導(dǎo)致脛骨軟骨發(fā)育不良。血清中OPG水平、Ca2+濃度和ALP活性均顯著降低，進(jìn)一步證實(shí)了骨代謝受到抑制。Wu等[75]通過(guò)人乳腺癌細(xì)胞MDA-MB-231和小鼠成骨細(xì)胞MC3T3-E1共培養(yǎng)系統(tǒng)的研究結(jié)果表明，與未經(jīng)處理的共培養(yǎng)物相比，馬錢子堿(brucine)處理顯著提高了共培養(yǎng)物中OPG/RANKL mRNA表達(dá)比率和OPG/RANKL蛋白比率，說(shuō)明馬錢子堿可通過(guò)調(diào)節(jié)成骨細(xì)胞中OPG和RANKL的表達(dá)和分泌來(lái)間接控制破骨細(xì)胞，從而抑制破骨細(xì)胞的分化和骨吸收功能。Hou等[76]將雌性Sprague-Dawley大鼠進(jìn)行卵巢切除術(shù)，分別用10、100、1000和2000 mg/kg /d等劑量的乳鐵蛋白(lactoferrin, LF)進(jìn)行口服治療，飼喂6個(gè)月后發(fā)現(xiàn)，LF劑量依賴性地增加了Ovx大鼠骨體積、骨小梁厚度和骨小梁數(shù)目，減少了骨小梁分離；此外，與未經(jīng)處理的Ovx大鼠相比，更高劑量的LF (1000 mg/kg/d和2000 mg/kg/d)顯著增加了骨密度，且總體上LF處理顯著提高了Ovx大鼠mRNA水平，抑制了mRNA水平；這些結(jié)果表明，口服LF可保留骨質(zhì)并改善骨骼的微結(jié)構(gòu)，且LF可能通過(guò)OPG/RANKL/RANK途徑的調(diào)節(jié)來(lái)增強(qiáng)骨形成，減少骨吸收及骨質(zhì)流失。據(jù)Ma等[77]發(fā)現(xiàn)220 mg/kg或440 mg/kg的1,6-二磷酸果糖鍶(FDP-Sr)治療能顯著提高Ovx大鼠的骨密度，改善骨微結(jié)構(gòu)和骨強(qiáng)度，且用FDP-Sr治療以劑量依賴性方式降低了血清中RANKL水平，增加了OPG水平，也顯著下調(diào)了骨髓中的表達(dá)和上調(diào)了表達(dá)，結(jié)果表明，F(xiàn)DP-Sr對(duì)絕經(jīng)后骨質(zhì)疏松癥的有效治療，其部分作用是通過(guò)OPG-RANKL-RANK途徑減少破骨細(xì)胞的生成完成。可見(jiàn)，OPG/RANKL的比值可調(diào)節(jié)骨吸收，OPG-RANK-RANKL信號(hào)通路在調(diào)節(jié)動(dòng)物骨形成和骨吸收的過(guò)程中起著至關(guān)重要的作用。

1.5 FGF信號(hào)通路

成纖維細(xì)胞生長(zhǎng)因子(fibroblast growth factor, FGF)信號(hào)通路已被證實(shí)在調(diào)節(jié)成骨細(xì)胞和成纖維細(xì)胞的增殖和分化、成骨以及許多其他重要的細(xì)胞過(guò)程中發(fā)揮著重要的作用，包括血管生成和傷口愈合[78]。

此外，F(xiàn)GF信號(hào)通路在調(diào)節(jié)骨祖細(xì)胞膜內(nèi)和軟骨內(nèi)骨化的信號(hào)傳遞過(guò)程中發(fā)揮著至關(guān)重要的作用[79]。由于FGF通路對(duì)成骨細(xì)胞分化的刺激作用以及對(duì)成骨細(xì)胞分化的抑制作用，表明FGF信號(hào)通路對(duì)成骨細(xì)胞成熟過(guò)程的影響是階段性的[80]，且顱骨和長(zhǎng)骨生長(zhǎng)異常多與FGF信號(hào)通路的突變有關(guān)[81]。

在23個(gè)FGF家族成員中，一些FGF在成骨過(guò)程中起著關(guān)鍵作用。例如，F(xiàn)GF2磷酸化激活Runx2，可影響骨形成[82]。此外，已有研究表明FGFR2 (FGF receptor 2)也參與了骨生長(zhǎng)的正向調(diào)控和成骨細(xì)胞的合成代謝功能[83]。FGFR3可通過(guò)調(diào)節(jié)成骨細(xì)胞分化來(lái)影響骨骼的骨密度和皮質(zhì)骨厚度[84]。FGF9和FGF18的表達(dá)也顯著影響胚胎骨形成[85]。

Kanda等[86]發(fā)現(xiàn)大鼠骨髓細(xì)胞在含堿性成纖維細(xì)胞生長(zhǎng)因子(basic fibroblast growth factor, bFGF)培養(yǎng)基中培養(yǎng)后，細(xì)胞數(shù)量顯著增加，細(xì)胞膨脹，BMP2和骨橋蛋白表達(dá)明顯增加。Furuya等[87]研究發(fā)現(xiàn)水凝膠bFGF治療骨折缺損后，小鼠骨密度較高，骨礦化率較高，和基因表達(dá)上調(diào)。D’mello等[88]研究表明，轉(zhuǎn)染編碼FGF2蛋白(PEI-pFGF2)的聚乙烯亞胺納米復(fù)合物(nanoplexes)的骨髓基質(zhì)細(xì)胞(BMSCs)中的基因高表達(dá)。Khorsand等[89]在糖尿病兔()模型中也開(kāi)發(fā)了相同的nanoplex，用于將FGF2和BMP2蛋白遞送到缺陷部位。結(jié)果表明，與單純植入膠原支架的PEI-pBMP2相比，植入膠原支架內(nèi)的PEI-(pBMP2 + pFGF2)可顯著改善骨再生。據(jù)Charles等[90]報(bào)道，在顱骨缺損的年老小鼠中，向BMP2中添加FGF2聯(lián)合治療后，小鼠骨缺損中心區(qū)域的骨填充增強(qiáng)，且骨體積增加。該研究表明，相對(duì)于單獨(dú)的BMP2或FGF2，低劑量FGF2和低劑量BMP2聯(lián)合應(yīng)用有可能增加老年小鼠的骨愈合能力。這些結(jié)果表明BMP2和FGF2協(xié)同作用可促進(jìn)骨修復(fù)。Yuan等[91]研究發(fā)現(xiàn)，單獨(dú)的BMP4/7顯著促進(jìn)了BMSCs的增殖，同時(shí)，它也促進(jìn)或抑制了BMSCs的成骨分化，而B(niǎo)MP4/7和bFGF的協(xié)同作用顯著促進(jìn)了BMSCs的增殖和成骨分化，協(xié)同作用的治療取決于劑量和時(shí)間。BMP4/7和bFGF的合理組合可以促進(jìn)BMSCs的增殖和成骨分化。綜上所述，BMP和FGF協(xié)同作用對(duì)成骨過(guò)程的調(diào)節(jié)起重要作用。

1.6 其他骨代謝重要信號(hào)通路

1.6.1 Notch信號(hào)通路

Notch信號(hào)通路作為一種進(jìn)化上高度保守的配體受體信號(hào)通路，在細(xì)胞存活、增殖、分化以及發(fā)育過(guò)程中的命運(yùn)決定、穩(wěn)態(tài)等方面發(fā)揮著重要的機(jī)制作用[92]。Notch信號(hào)通路在骨骼生長(zhǎng)發(fā)育中起著對(duì)成骨細(xì)胞的直接誘導(dǎo)作用。而骨祖細(xì)胞中Notch信號(hào)通路受到抑制可導(dǎo)致骨髓源性間充質(zhì)干細(xì)胞的損耗，并與各年齡段骨質(zhì)流失有關(guān)[93,94]。Pan等[95]研究發(fā)現(xiàn)，活化的B淋巴細(xì)胞通過(guò)激活Notch信號(hào)來(lái)抑制BMSC的成骨作用，當(dāng)B淋巴細(xì)胞被滅活或Notch信號(hào)被抑制時(shí)，BMSC的成骨作用將部分恢復(fù)。He等[96]在小鼠細(xì)胞實(shí)驗(yàn)中發(fā)現(xiàn)，抑制Notch1減少了BMSC的增殖并促進(jìn)其成骨分化。這些結(jié)果表明Notch信號(hào)通路在BMSC分化過(guò)程中受到抑制，說(shuō)明Notch信號(hào)通路對(duì)BMSC成骨分化具有抑制作用。另一方面，F(xiàn)ukushima等[97]研究發(fā)現(xiàn)，Notch 2是破骨細(xì)胞重塑刺激物，它在破骨細(xì)胞分化過(guò)程中調(diào)節(jié)活化T細(xì)胞核因子c1(NFAT-c1)的啟動(dòng)子并誘導(dǎo)破骨細(xì)胞形成。因此，Notch信號(hào)在骨骼發(fā)育中起著不可或缺的作用。

1.6.2 Hedgehog信號(hào)通路

Hedgehog(Hh)信號(hào)通路是調(diào)節(jié)骨骼發(fā)育的關(guān)鍵。目前在哺乳動(dòng)物中已經(jīng)確定了3種Hh：Sonic Hh(Shh)，Indian Hh(Ihh)和Desert Hh(Dhh)[98]。其中，Ihh是在發(fā)育中的骨骼內(nèi)唯一發(fā)現(xiàn)的Hh，Ihh由軟骨細(xì)胞分泌，調(diào)節(jié)軟骨細(xì)胞的增殖和分化，對(duì)骨骼生長(zhǎng)至關(guān)重要[99,100]。有研究發(fā)現(xiàn)，Hh信號(hào)通路可能通過(guò)增加和的表達(dá)來(lái)誘導(dǎo)MSC的成骨分化，并抑制MSC分化為脂肪細(xì)胞[101]。Zaman等[102]研究顯示，在內(nèi)源性抗凋亡蛋白humanin(HN)高表達(dá)小鼠、HN處理的野生型小鼠和HN處理的培養(yǎng)小鼠跖骨中，糖皮質(zhì)激素(glucocorticoid, GC)誘導(dǎo)的骨生長(zhǎng)損傷和軟骨細(xì)胞凋亡被阻止，HN可通過(guò)靶向Hh途徑使GC誘導(dǎo)的骨生長(zhǎng)障礙受到抑制并恢復(fù)，而不會(huì)干擾GC所發(fā)揮的抗炎作用。可見(jiàn)，Hedgehog信號(hào)通路在調(diào)節(jié)成骨細(xì)胞分化和骨骼發(fā)育中起重要作用。

1.6.3 PI3K/Akt信號(hào)通路

PI3K/Akt信號(hào)通路是一種重要的有絲分裂信號(hào)通路，在生長(zhǎng)、存活、增殖和活性等多種細(xì)胞過(guò)程中發(fā)揮著重要作用[103]。在骨骼生長(zhǎng)發(fā)育中，PI3K信號(hào)及其下游靶點(diǎn)在骨形成和骨重塑中起著重要調(diào)控功能[104]。Ke等[105]研究表明，川續(xù)斷皂苷VI (asperosaponin VI, ASA VI)促進(jìn)了去卵巢小鼠BMSC的增殖，增強(qiáng)了ALP活性，并促進(jìn)了鈣結(jié)節(jié)的生成；此外，ASA VI增強(qiáng)了和的表達(dá)，而經(jīng)LY294002 (阻斷PI3K/Akt信號(hào)通路的蛋白激酶抑制劑)處理則降低了以上成骨作用，并降低了ASA VI誘導(dǎo)的p-Akt (磷酸化Akt)水平。這些結(jié)果表明，ASA VI通過(guò)作用于PI3K/Akt信號(hào)通路來(lái)促進(jìn)Ovx的BMSC的成骨分化?？梢?jiàn)，在動(dòng)物骨骼生長(zhǎng)發(fā)育中激活PI3K/Akt信號(hào)通路可促進(jìn)BMSC的成骨分化。

1.6.4 鈣離子信號(hào)通路

鈣離子(Ca2+)在骨骼中起著重要的結(jié)構(gòu)作用，且Ca2+信號(hào)在成骨細(xì)胞分化過(guò)程中起著重要作用。在骨重塑過(guò)程中，Ca2+作為礦物相的成分，以游離離子的形式不斷釋放到細(xì)胞外環(huán)境中[106]。因此，Ca2+持續(xù)可作用于成骨細(xì)胞和骨祖細(xì)胞發(fā)揮生物學(xué)功能。Ca2+進(jìn)入鈣通道介導(dǎo)的細(xì)胞，Runx2起中介作用，激活磷脂酶C(PLC)和肌醇-1,4,5-三磷酸肌醇(IP3)信號(hào)[107]，進(jìn)而促進(jìn)細(xì)胞內(nèi)存儲(chǔ)Ca2+的釋放，從而促進(jìn)骨骼的生長(zhǎng)發(fā)育。細(xì)胞外鈣敏感受體(Calcium- Sensing Receptor, CaR)是一種G蛋白偶聯(lián)受體，在調(diào)節(jié)細(xì)胞外鈣穩(wěn)態(tài)中起重要作用，Liu等[108]研究表明，高鈣血癥的減少在預(yù)防缺陷(CaR)小鼠的早期致死性中起關(guān)鍵作用，且CaR小鼠軟骨內(nèi)骨形成缺陷是由于血清鈣濃度顯著升高、血清磷濃度和骨骼甲狀旁腺激素相關(guān)蛋白水平降低所致。Chang 等[109]研究表明，骨骼中的缺失會(huì)導(dǎo)致嚴(yán)重的骨骼缺陷，而軟骨細(xì)胞(軟骨生成細(xì)胞)中的缺失導(dǎo)致胚胎第13天(E13)前死亡，但在E16~E18之間誘導(dǎo)小鼠軟骨細(xì)胞特異性缺失是可行的，但顯示小鼠生長(zhǎng)板發(fā)育延遲；這些結(jié)果顯示在早期胚胎發(fā)生和骨骼發(fā)育中起著關(guān)鍵作用。綜上所述，鈣離子受體敲除小鼠實(shí)驗(yàn)證明了鈣離子信號(hào)對(duì)骨發(fā)育非常重要。

1.6.5 Hippo信號(hào)通路

Hippo信號(hào)是調(diào)節(jié)器官大小和組織再生的主要因素，近年來(lái)的一些研究表明Hippo信號(hào)通路在調(diào)節(jié)骨形成方面發(fā)揮作用。Wang等[110]通過(guò)體外實(shí)驗(yàn)研究表明，小鼠BMSCs包括遷移和成骨的生物學(xué)功能與Hippo途徑的關(guān)鍵下游效應(yīng)物YAP(Yes相關(guān)蛋白)的表達(dá)增強(qiáng)有關(guān)。Chen等[111]發(fā)現(xiàn)，在成骨培養(yǎng)條件下，BMSCs中Hippo信號(hào)的激活抑制了成骨分化。Hippo信號(hào)通路對(duì)于骨骼發(fā)育的具體調(diào)控機(jī)制還不明確，還需開(kāi)展更多的相關(guān)研究。

2 結(jié)語(yǔ)與展望

動(dòng)物骨骼生長(zhǎng)發(fā)育及骨代謝受BMP/Smads、TGF-β、Wnt/β-catenin、OPG/RANKL/RANK和FGF等多條關(guān)鍵信號(hào)通路調(diào)控，這些信號(hào)通路通過(guò)直接或間接作用于Runx2或β-catenin等關(guān)鍵轉(zhuǎn)錄因子而彼此相互聯(lián)系、相互影響，從而組成了復(fù)雜的調(diào)控網(wǎng)絡(luò)(骨代謝調(diào)控的關(guān)鍵信號(hào)通路圖見(jiàn)圖1)。該網(wǎng)絡(luò)協(xié)同參與了骨代謝過(guò)程的調(diào)控，維持骨穩(wěn)態(tài)。盡管目前對(duì)骨代謝相關(guān)信號(hào)通路的研究較多，也取得了一些重要的研究成果，但對(duì)于調(diào)控動(dòng)物骨代謝的分子機(jī)制仍未闡明清晰。隨著生命科學(xué)的不斷發(fā)展，在不遠(yuǎn)的將來(lái)能夠解析骨代謝調(diào)控的完整分子機(jī)制，只有理解了這些信號(hào)通路的分子作用機(jī)制，并闡明這些信號(hào)通路傳導(dǎo)途徑之間的相互作用，才能為動(dòng)物病理性骨骼的治療奠定基礎(chǔ)。

此外，本文介紹了中草藥及其提取物可通過(guò)這些信號(hào)通路調(diào)節(jié)骨形成或骨吸收過(guò)程，從而維持骨代謝的平衡。目前已有較多研究表明，淫羊藿()、補(bǔ)骨脂(.)、當(dāng)歸()、山藥()、杜仲()等單體及其提取物，或是由多味單劑組成的方劑如更年春、密骨膠囊等均對(duì)動(dòng)物骨骼的生長(zhǎng)發(fā)育起作用，說(shuō)明中草藥在防治動(dòng)物病理性骨骼方面具有廣闊的前景。但動(dòng)物骨骼疾病的分子機(jī)制復(fù)雜，中草藥對(duì)于骨代謝相關(guān)信號(hào)通路的調(diào)控研究還處于初始階段，還需進(jìn)一步深入研究。將中草藥應(yīng)用與動(dòng)物骨骼發(fā)育和骨代謝的分子機(jī)制研究相結(jié)合，不僅可以深入揭示中草藥防治骨骼疾病的機(jī)制，還能為動(dòng)物骨骼疾病的防治提供依據(jù)，使中草藥的應(yīng)用前景更廣闊。

圖1 骨代謝調(diào)控的關(guān)鍵信號(hào)通路圖

TGF-β信號(hào)通路通過(guò)Smad2/3路徑調(diào)節(jié)BMSCs的增殖、分化及其成骨細(xì)胞分化；FGF信號(hào)通路中FGF和FGFR可調(diào)節(jié)BMSCs的增殖和成骨分化；BMP/Smads信號(hào)通路通過(guò)激活Smads1/5/8，結(jié)合Smad4，再與Runx2和OSX等相互作用，調(diào)節(jié)成骨細(xì)胞分化與骨重建；Wnt/β-catenin信號(hào)通路通過(guò)Wnt蛋白與Frizzled 和Lrp5/6結(jié)合，激活β-catenin并將其轉(zhuǎn)移到細(xì)胞核與TCF/LEF等相互作用，激活Wnt靶基因的轉(zhuǎn)錄，從而調(diào)控成骨細(xì)胞的增殖、分化及骨形成；OPG/RANKL/RANK信號(hào)通路中OPG和RANKL競(jìng)爭(zhēng)性結(jié)合，阻止RANKL和RANK之間的結(jié)合，通過(guò)調(diào)節(jié)OPG/RANKL比值來(lái)調(diào)控骨吸收過(guò)程。該5條關(guān)鍵信號(hào)通路共同參與調(diào)節(jié)動(dòng)物骨骼的生長(zhǎng)發(fā)育與骨代謝平衡。

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Progress on signal pathways related to bone metabolism in animals

Jingying Zhao1, Xiaohua Duan1,2, Qiuting Wang1, Ying Huang1, Junjing Jia1, Tengfei Dou1

Bone is a hard organ that makes up vertebrate endoskeleton, which plays a role in movement, support and protection for the body. The normal growth and development of bone is in the dynamic balance of bone metabolism, which is composed of bone formation and bone absorption. This balance is very important for maintaining bone mass and mineral homeostasis. In the process of bone growth and metabolism, there are many signaling pathways regulating bone formation and absorption, such as BMP (bone morphogenetic protein)/SMADs, TGF-β (transforming growth factor β), Wnt/β-catenin, OPG (osteoprotegerin)/RANKL (receptor activator of NF-κB ligand)/RANK (receptor activator of NF-κB), FGF (fibroblast growth factor) and Notch signaling pathway. These signaling pathways have complex regulatory mechanisms and are involved in the regulation of bone metabolism. In this review, we summarize the mechanism and research progress of signal pathways that play key regulatory roles in the process of animal bone metabolism, thereby laying a foundation for research in animal bone metabolism.

bone metabolism; signaling pathway; bone formation; bone resorption

2020-03-11;

2020-06-14

國(guó)家自然科學(xué)基金項(xiàng)目(編號(hào)：U1702232)，云南省創(chuàng)新團(tuán)隊(duì)項(xiàng)目(編號(hào)：2019HC011)，云南省科技廳南希·萊恩院士工作站項(xiàng)目(編號(hào)：2017IC048)，云嶺產(chǎn)業(yè)技術(shù)領(lǐng)軍人才培養(yǎng)和云南省博士研究生學(xué)術(shù)新人獎(jiǎng)資助[Supported by National Natural Science Foundation of China (No. U1702232), Yunnan Innovation Team Project (No. 2019HC011), Nancy Lane Academician Workstation Project of Yunnan Science and Technology Department (No. 2017IC048), Yunling Industrial Technology Leader Training, and New Academic Award for Doctoral Candidates in Yunnan Province.]

趙凈穎，在讀碩士研究生，專業(yè)方向：動(dòng)物營(yíng)養(yǎng)與飼料科學(xué)。E-mail: 1849680658@qq.com

豆騰飛，講師，研究方向：動(dòng)物遺傳育種與繁殖。E-mail: tengfeidou@sina.com

10.16288/j.yczz.20-066

2020/7/30 9:38:52

URI: https://kns.cnki.net/kcms/detail/11.1913.R.20200728.1634.001.html

(責(zé)任編委: 張雷)